Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice.

BACKGROUND: Immune processes contribute to the development of obesity and its complications, such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Approaches that target the inflammatory response are promising therapeutic strategies for obesity. In this context, we recently demonstrated that the interaction between the costimulatory protein CD40 and its downstream adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes adipose tissue inflammation, insulin resistance and hepatic steatosis in mice in the course of diet-induced obesity (DIO). METHODS: Here we evaluated the effects of a small-molecule inhibitor (SMI) of the CD40-TRAF6 interaction, SMI 6860766, on the development of obesity and its complications in mice that were subjected to DIO. RESULTS: Treatment with SMI 6860766 did not result in differences in weight gain, but improved glucose tolerance. Moreover, SMI 6860766 treatment reduced the amount of CD45(+) leucocytes in the epididymal adipose tissue by 69%. Especially, the number of adipose tissue CD4(+) and CD8(+) T cells, as well as macrophages, was significantly decreased. CONCLUSIONS: Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile.

[Changes in social interaction following a CVA. Practical experience at a rehabilitation center]. / Veranderingen in de sociale interactie na een CVA. Praktijkervaringen in een revalidatiecentrum.

After a cerebral infarct the joint efforts in our center for rehabilitation 'Hoensbroeck' are intended to help the patient regain his equilibrium. The loss of a number of bodily functions results in limitations in the activities of daily living. The way in which the patient copes with these impairments will finally determine the seriousness of the handicap. This adjustment to the disease and its consequences takes place in a social context. In this contribution special attention is paid to the influence of cognitive functional disorders on the interaction process. The importance of timely diagnosis and support is also noted. In this connection the partner group being part of the treatment as applied in 'Hoensbroeck' for some time is introduced. Finally the recent foundation is mentioned of a stroke patients association.

Dependency of MCV and haemoglobin concentration on plasma vitamin B12 levels in relation to sex and age.

In a retrospective study of 872 men and 1474 women we determined the relationship between serum vitamin B12 concentration and mean values for Hb and MCV, which were known for 68% of the men and 72% of the women. In both sexes there was a distinct decrease in the mean Hb at serum vitamin B12 concentrations < 0.05 nmol/l. However, the mean MCV was already raised by 4-5 fl at serum vitamin B12 levels < 0.16 nmol/l in men and < 0.11 nmol/l in women, and the percentage of patients with macrocytosis (defined as MCV > 100 fl) also increased significantly at these levels. To find out whether these relationships were age-dependent, male and female patients were split into groups of 20-70 years old and older persons. The mean MCV in men aged 20-70 years increased at a serum vitamin B12 level < 0.16 nmol/l, whereas in older men an increase in mean MCV occurred only at vitamin B12 levels < 0.11 nmol/l. In women, the mean MCV for both age groups increased significantly at a serum vitamin B12 level < 0.11 nmol/l. We conclude that haematological signs of B12 deficiency arise at different serum vitamin B12 concentrations in men and women and that only in men is there an age dependency.